P ROTEASOME I NHIBITORS IN M ANTLE C ELL L YMPHOMA Owen A. O’Connor, M.D., Ph.D. Founding Director, Center for Lymphoid Malignancies Professor of Medicine and Developmental Therapeutics The New York Presbyterian Hospital Columbia University College of Physicians and Surgeons New York, N.Y. 2nd Post-Graduate Lymphoma Conference Rome, Italy March 23
P ROTEASOME I NHIBITORS IN M ANTLE C ELL L YMPHOMA • Proteasome Inhibitors and the Proteasome : A Gentle Reminder • Mantle Cell Lymphoma • Indolent Lymphomas • Diffuse Large B-Cell Lymphoma • Peripheral T-Cell Lymphoma • Summary : Novel - Novel Prospects
P ROTEASOME I NHIBITORS IN L YMPHOMA • Rationale – Disrupts pathways involved in pathogenesis of lymphoma – Preclinical models show sensitivity of lymphoma cell lines to proteasome inhibitors Carfilzomib (PR-171) NPI-0052 Bortezomib Irreversible inhibitor Irreversible inhibitor Reversible inhibitor Phase I testing Early phase I testing Approved for MCL O’Connor. Clin Lymphoma Myeloma . 2005;6:191; Leonard. Int J Cancer . 2006;119:971; Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 2003; Demo. Cancer Res . 2007;67:6383; Ahn. Blood . 2007 [Epub ahead of print]; Stewart. ASCO 2007 (abstr 8003); Chauhan. Br J Cance r. 2006;95:961.
E FFECTS OF B ORTEZOMIB ON T UMOR AND S TROMAL T ARGETS : P LEIOTROPIC D RUGS Apoptosis Microenvironment ↓ NF - B, ↓ cytokines, ↑ p53, ↑ p21, ↑ Bax, ↑ tBID , ↑ Bcl -2, ↓ cell adhesion molecules, ↓ VEGF, ↓ TNF - α ↓ MAPK, ↓ survivin, ↓ XIAP, ↓ cIAP ↑ Caspases Cell-Cycle Arrest Stress Response ↑ p53, ↑ p21, ↑ p27, ↓ DNA repair, ↓ Pgp, ↓ NF - B, ↓ MAPK, ↑ TopII , ↑ TopI, ↑ cyclins A/B/D/E, ↓ NF - B, ↓ MAPK, ↑ c -fos/c-jun , ↑ Myc, chemo- and ↑ beta catenin radiosensitization MAPK=mitogen-activated protein kinase; NF- B=nuclear factor kappa B. Kyle. N Engl J Med . 2004;351:1860; Adams. Drug Disc Today . 2003;8:307; Adams. Invest New Drugs . 2000;18:109; Voorhees. Clin Cancer Res . 2003;6:6316; Leonard. Int J Cancer . 2006;119:971; Richardson. Cancer Control . 2003;10:361; Ling. Mol Cancer Ther . 2002;1:841.
N OVEL T ARGETS /T HERAPIES : P ROTEASOME I NHIBITORS • Proteasome Inhibitors and the Proteasome : A Gentle Reminder • Mantle Cell Lymphoma • Indolent Lymphomas • Diffuse Large B-Cell Lymphoma • Peripheral T-Cell Lymphoma • Summary: Novel - Novel Prospects
S INGLE - AGENT A CTIVITY OF B ORTEZOMIB IN M ANTLE C ELL L YMPHOMA Evaluable Study Bortezomib Regimen Patients (n) CR/CRu PR OR O’Connor 1.5 mg/m 2 days 1, 4, 8, 11 37 13% 27% 40% (ICML 2005) 21-day cycle 1.5 mg/m 2 days 1, 4, 8, 11 Goy 29 21% 21% 41% (JCO 2005) 21-day cycle 1.3 mg/m 2 days 1, 4, 8, 11 Strauss/Lister 24 4% 25% 29% (IMCL 2005) 21-day cycle 1.3 mg/m 2 days 1, 4, 8, 11 Belch 13 untreated 0% 46% 46% (ASH 2004) 21-day cycle 15 treated 7% 40% 47% PINNACLE 1.3 mg/m 2 days 1, 4, 8, 11 141 8% 26% 33% ( ASCO 2005) 21-day cycle
Bortezomib in Relapsed / Refractory MCL Dose n ORR CRR Fisher 1.3 BIW 141 31% 8% JCO 2006 Goy Ann Onc 2009
LYM-3002: P HASE III R ANDOMIZED , O PEN -L ABEL , M ULTI -C ENTER T RIAL OF R-CHOP VS . V C R-CAP IN P REVIOUSLY U NTREATED MCL I NELIGIBLE FOR SCT Newly diagnosed MCL patients: Measurable stage II – IV MCL ECOG PS 0 – 2 Ineligible or not considered for BMT Randomization 1:1 stratified by: IPI score (0 – 1, 2, 3, 4 – 5) Disease stage at diagnosis (II, III, IV) 6 – 8 x 21-day cycles (up to 8 cycles if investigator-assessed VcR-CAP response first documented at cycle 6) R-CHOP Rituximab 375 mg/m 2 IV d 1 Rituximab 375 mg/m 2 IV d 1 Cyclophosphamide 750 mg/m 2 IV d 1 Cyclophosphamide 750 mg/m 2 IV d 1 Doxorubicin 50 mg/m 2 IV d 1 Doxorubicin 50 mg/m 2 IV d 1 Prednisone 100 mg/m 2 PO d 1 – 5 Prednisone 100 mg/m 2 PO d 1 – 5 Vincristine 1.4 mg/m 2 (max. 2 mg) IV d 1 Bortezomib 1.3 mg/m 2 IV d 1, 4, 8, 11 Cavalli F et al. ASCO 2014, abstract #8500
LYM-3002: P HASE III R ANDOMIZED , O PEN -L ABEL , M ULTI - C ENTER T RIAL OF R-CHOP VS . V C R-CAP IN P REVIOUSLY U NTREATED MCL I NELIGIBLE FOR SCT Secondary outcomes: Response and DOR by IRC, TTP, TTNT, TFI, OS R-CHOP VcR-CAP HR Response-evaluable population P (n=244) (n=243) CR+CRu*, % 42 53 OR 1.69 0.007 ORR (CR+CRu+PR), % 90 92 OR 1.43 0.275 Median time to initial response, mos 1.6 1.4 HR 1.54 <0.001 Median DOR (CR+CRu+PR), mos 15.1 36.5 NA NA In patients with CR+CRu* 18.5 42.1 NA NA Median duration of CR/CRu, mos 18.0 42.1 NA NA Median TTP by IRC, mos 16.1 30.5 HR 0.58 <0.001 By investigator, mos 16.8 35.0 HR 0.47 <0.001 Median time to next therapy (TTNT), mos 24.8 44.5 HR 0.50 <0.001 Median treatment-free interval (TFI), mos 20.5 40.6 HR 0.50 <0.001 Median OS, mos 56.3 NR HR 0.80 0.173 – – 4-year OS rate, % 53.9 64.4 *CR/CRu verified by bone marrow and LDH; † data shown are odds ratio (OR), except for hazard ratio (HR) for time to response; NA, not applicable; NR: not reached Cavalli F et al. ASCO 2014, abstract #8500
LYM-3002: P HASE III R ANDOMIZED , O PEN -L ABEL , M ULTI - C ENTER T RIAL OF R-CHOP VS . V C R-CAP IN P REVIOUSLY U NTREATED MCL I NELIGIBLE FOR SCT 59% improvement in PFS by IRC with VcR-CAP vs R-CHOP (median follow-up 40 mos) R-CHOP VcR-CAP Events, n 165 133 100 R-CHOP Median PFS, months 14.4 24.7 (95% CI) (12.0, 16.9) (19.8, 31.8) VcR-CAP progression-free, % 80 Patients alive and HR (95% CI) 0.63 (0.50, 0.79) P-value <0.001 60 40 20 0 0 6 12 18 24 30 36 42 48 54 60 66 Months from randomization Number of patients at risk: R-CHOP 244 181 116 79 55 36 22 16 9 3 0 0 VcR-CAP 243 187 146 122 94 66 42 28 17 8 1 0 Median PFS by investigator was 16.1 vs 30.7 mos with R-CHOP vs VcR-CAP; 307 (63%) events; HR 0.51, p<0.001; 96% improvement with VcR-CAP At Cost of More Toxicity : Neuropathy Cavalli F et al. ASCO 2014, abstract #8500
LYM-3002: P HASE III R ANDOMIZED , O PEN -L ABEL , M ULTI - C ENTER T RIAL OF R-CHOP VS . V C R-CAP IN P REVIOUSLY U NTREATED MCL I NELIGIBLE FOR SCT Secondary outcomes: OS (Median follow-up 40 mos) R-CHOP VcR-CAP Events, n 87 71 Median OS, months 56.3 Not reached 100 (95% CI) (47.2, NE) (56.0, NE) HR (95% CI) 0.80 (0.59, 1.10) 80 Patients alive, % P-value 0.173 60 40 R-CHOP VcR-CAP 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months from randomization Number of patients at risk: R-CHOP 244 214 204 192 177 141 100 70 43 21 7 1 0 VcR-CAP 243 212 200 191 171 140 100 75 52 28 8 1 0 There was a trend to prolonged survival with VcR-CAP (not statistically significant) Cavalli F et al. ASCO 2014, abstract #8500
E1411 - Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma in patients age 60 Randomized phase II, N ~ 328; 82 eligible per arm BR x 6 Rituximab R E G BVR x 6 Rituximab I S T R Lenalidomide BR x 6 A + Rituximab T I Lenalidomide O BVR x 6 + Rituximab N BR = Bendamustine, Rituximab V= Bortezomib BBR (VERTICAL) ; ORR 88%, complete response rate 53%, median PFS 15 mos ( Fowler, et al, JCO 2011)
P ROTEASOME I NHIBITORS IN M ANTLE C ELL L YMPHOMA : S UMMARY OF C LINICAL S TATUS • In lymphoma, MCL remains the only US FDA approval for the drug • Most use now has matured to combination use in R-CHOP and R-Bendamustine, though ECOG results are pending • Activity appreciated in MZL, PTCL, perhaps sub- types of DLBCL • Novel : novel combinations are proving interesting……
H OW D O W E I MPROVE THE M ERITS OF P ROTEASOME I NHIBITORS ? Make Better Ones Or Identify Synergistic Combinations (not predicated on genotoxic chemtherapy)
I XAZOMIB (MLN2238) • First orally bioavailable proteasome inhibitor in clinical trials • Binds to the chymotrypsin- like site of the 20S proteasome • Similar selectivity and potency to bortezomib, but shorter 20S proteasome dissociation half-life
P HASE 1 S TUDY OF IV I XAZOMIB IN L YMPHOMA • IV administration on days 1, 8, 15 of 28 days • 30 subjects with relapsed/refractory NHL – FL 11, DLBCL 5, PTCL 4, HL 3, MF 2, MCL 2, Other 2 • MTD determined to be 2.34 mg/m2 • DLTs: Neutropenia, diarrhea, renal failure • Most common AEs: fatigue (43%), diarrhea (33%), nausea, thrombocytopenia, rash (each 27%) • 26 evaluable for response, 5 responders (19%) – 1 CR (FL), 4 PRs (3 FL, 1 PTCL) Assouline et al. Blood Can J 2014
Carfilzomib • Tetrapeptide ketoepoxide-based irreversible inhibitor of the 20S proteasome. • Higher affinity for proteasome than bortezomib, and demonstrated activity in bortezomib resistant NHL cell lines • Phase 1 trial reached 20/27 mg/m2 on days 1,2, 8, 9, 15, 16 of a 28 day cycle. No MTD reached. • Anemia, thrombocytopenia, nausea, fatigue, constipation, pyrexia, cough, anorexia • Among 15 NHL, 5 SD (4 FL, 1 CLL/SLL)
Proteasome Inhibitors Synergize with BTK Targeted Drugs Dasmahapatra et al, Br J Haematol 2013 The bruton’s tyrosine kinase inhibitor ibrutinib synergized with the proteasome inhibitor carfilzomib and overcame immunoproteasome- mediated carfilzomib resistance in mantle cell lymphoma Ou, et al, AACR abstract #2432, 2013 Combinatorial drug screening identifies synergistic co- targeting of Bruton’s Tyrosine Kinase and the proteasome in Mantle Cell Lymphoma Axelrod, Ou, Brett et al, Leukemia 2013
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